The phenomenon of circadian rhythms in biology is well known, and circadian rhythms are exhibited by all eukaryotic plants and animals, including man. Biological rhythms are periodic fluctuations in biological properties over time; these include circadian as well as seasonal variations. Circadian, or approximately 24-hour, rhythms include the production of biological molecules such as hormones, the regulation of body temperature, and behaviors such as wakefulness, sleep and periods of activity. In nature, circadian rhythms are closely tied to environmental cues that impose a 24 hour pattern on many of these fluctuations. Experimental inquiry has established that when these cues are absent, most circadian rhythms have a periodicity of approximately 25 hours. Circadian rhythms that are not regulated by environmental cues are said to be free-running. The regulation of circadian rhythms by signals from the environment is said to involve entrainment of the circadian rhythms. The environmental signals that effect entrainment have been termed zeitgebers, an example of which is the light-dark cycle.
It is thought in the art that the control of circadian rhythms in mammals is mediated by a portion of the brain called the superchiasmatic nuclei (SCN). One of the major circadian rhythms, the pattern of wakefulness and sleep, is mediated by a feedback loop involving the retina, the SCN and the pineal gland. The pineal gland is primarily responsible for the production of melatonin, or N-acetyl-5-methoxytryptamine. Melatonin is believed to be the physiological mediator of sleep and wakefulness in mammals.
The disruption of circadian rhythms can result in a number of pathophysiological states in humans; the most common of these is jet lag. The use of melatonin to ameliorate the effects of jet lag has been described in the prior art.
U.S. Pat. Nos. 4,665,086 and 4,600,723 teach the use of melatonin to alleviate the symptoms of jet lag. These patents teach the use of 1-10 mg of melatonin, taken at destination bedtime, and again upon premature awakening in the middle of the night. A number of examples are disclosed in these patents, all of which involve travelers who take these doses of melatonin at destination bedtime and report the alleviation of the symptoms of jet lag.
Without wishing to be bound to this hypothesis, the present inventors believe that U.S. Pat. Nos. 4,665,086 and 4,600,723 are mistaken when they describe their use of exogenous melatonin as resulting in restoration of a circadian rhythm. Rather, the administration of exogenous melatonin taught by these patents should merely reinforce the (usual) rise in endogenous melatonin which occurs near the time of sleep onset. It is known that melatonin in high doses increases tiredness and the tendency to sleep (see Arendt et al. Neurosci. Lett. 45: 317-325, 1984; Arendt et al. CIBA Found. Symp. 117: 266-283, 1986). The present inventors believe that the effect described in U.S. Pat. Nos. 4,665,086 and 4,600,723 arises mainly from the soporific, hypnotic and sleep-inducing properties of melatonin administered at high doses, and that following the teachings of these patents would result in little, if any, change in the circadian rhythms of endogenous melatonin production.
Arendt et al. Ergonomics 30:1379-1393 (1987) disclose the administration of melatonin to alleviate jet lag. Exogenous melatonin is administered orally from 4 to 6 hours prior to the human's normal bedtime and taken upon awakening in the middle of the night. This schedule of melatonin administration was reported subjectively both to improve sleep quality and decrease sleep latency and to promote a more rapid reestablishment of the circadian rhythms of endogenous melatonin production. The present inventors believe that the data presented do not support the latter conclusion. No prior art references known to the present inventors teach melatonin administration more than 6 hours prior to the patient's normal bedtime to alleviate jet lag in a human. No prior art references known to the present inventors relate exogenous melatonin administration to the time interval between such administration and the time of endogenous melatonin onset in humans.
Armstrong et al. Experientia 45:932-938 (1989) disclose that in rats the effects of exogenous melatonin administration on the circadian rhythm of the sleep/wake cycle depends on the time of administration relative to the sleep/wake cycle, and that the effect was greatest when exogenous melatonin was administered several hours before the effective start of the nocturnal activity cycle. However, these authors were unable to demonstrate phase-delay shifts or a phase-response curve (PRC); that is, they did not relate the timing of exogenous melatonin administration to the time of the endogenous melatonin onset.
Gwinner and Benzinger J. Comp. Physiol. 126: 123-129 (1978) teach that daily injections of melatonin can entrain the activity/rest cycle in birds.
Underwood J. Pineal Res. 3:187-196 (1986) disclosed a PRC for melatonin in the lizard Sceloporus occidentalis.
Mallo et al. Acta Endocrinol. 119: 474-480 (1988) teach the adminstration of 8 mg of melatonin to humans, one hour before bedtime over a course of four days, results in a slight phase advance three days after cessation of the melatonin treatment.
Entrainment and regulation of the melatonin circadian rhythm has thus been demonstrated in a number of animal species. The present inventors are the first to disclose a PRC for melatonin in a human, and perhaps in any mammalian species. The ability to effect an actual change in phase of the circadian rhythm would be useful for the alleviation of a number of circadian rhythm related disorders, as will be further discussed in the embodiments below. This application discloses a method to advance or delay the onset of the production of endogenous melatonin, and hence actually affect the regulation of an endogenous circadian rhythm in man.